Bicyclic β-lactam antibiotics

ABSTRACT

A method for preparing 2-amino- beta -lactams which are substituted by readily-removed protecting groups is provided. According to this invention, an acyl-2-amino- beta -lactam is further acylated with a different acyl group and is subsequently treated with base to provide a protected 2-amino  beta -lactam with a more desirable protecting group.

This application is a division, of application Ser. No. 07/588,381,filed Sep. 26, 1990 now U.S. Pat. No. 5,142,039, which is a division ofapplication Ser. No. 07/410,208 filed Sep. 21, 1989, now U.S. Pat. No.4,983,732, which is a division of application Ser. No. 07/080,354, filedJul. 21, 1987, now abandoned.

BACKGROUND OF THE INVENTION

The clinically useful β-lactam antibiotics include a wide variety ofcompounds: cephalosporins such as cephalexin, cefaclor, and cefamandol;totally synthetic "oxa"-cephalosporins such as moxalactam; and a varietyof monocyclic β-lactams as well as bicyclic β-lactams. Because theβ-lactam antibiotics represent such an important therapeutic class,considerable effort is directed toward more efficient methods for theirpreparation.

Summary

This invention relates to a process for preparing β-lactam antibioticintermediates. In particular, it relates to a process for the selectiveN-deacylation of an N-(alkyl, arylalkyl, or alkenyl)oxycarbonylN-acylamino substituted β-lactam to an N-(alkyl, arylalkyl, oralkenyl)oxycarbonylamino substituted β-lactam. The process affords readyexchange of the N-acyl group of an N-acylamino substituted β-lactam to aprotected amino substituted β-lactam wherein the amino-protecting groupis readily removable. The process thus provides protected-aminosubstituted β-lactam compounds which, upon deprotection, afford freeamino substituted β-lactams. The latter are valuable intermediates toantibiotic compounds.

In an example of the process, p-nitrobenzyl7β-phenoxyacetylamino-3-methyl-3-cephem-4-carboxylate is reacted in aninert solvent with di-t-butyldicarbonate in the presence of4-dimethylaminopyridine to form p-nitrobenzyl7β-[(N-t-butyloxycarbonyl-N-phenoxy-acetyl)amino]-3-methyl-3-cephem-4-carboxylate.The latter is treated in an inert solvent at room temperature withN,N-diethylethylene diamine to provide p-nitrobenzyl7β-(t-butyloxycarbonylamino)-3-methyl-3-cephem-4-carboxylate.

Also provided by this invention are novel disubstituted-aminosubstituted β-lactams.

The process provided herein is an alternative method to knownN-deacylation methods employed with β-lactam compounds. For example,there are instances when the known imino halide, imino ether cleavagemethod results in low yields or undue decomposition. In such cases, thepresent process can be an attractive alternative.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing a protected aminosubstituted β-lactam compound of Formula (1) ##STR1## wherein R isallyloxycarbonyl, t-butoxycarbonyl, naphthyloxycarbonyl,trichloroethyloxycarbonyl, p-nitrobenzyloxcarbonyl,benzhydryloxycarbonyl, p-methoxybenzyloxcarbonyl,o-nitrobenzyloxycarbonyl or acetoxy; where A and A', when takenseparately, are defined as follows: A is C₁ to C₆ alkyl, C₁ to C₆substituted alkyl or a group of the formula --S--C₁ -C₄)CO₂ R', whereinR' is hydrogen or a carboxy-protecting group; A' is hydrogen or anamide-protecting group; and when A and A' are taken together, they forma group of the formula ##STR2## wherein R¹ is a carboxy-protectinggroup; X is sulfur, --CH₂ --, or oxygen and R² is hydrogen or asubstitutent group as defined hereinafter;

which comprises:

reacting of a compound of Formula (2): ##STR3## wherein A and A' are thesame as defined hereinabove and R⁴ is phenoxyacetyl, phenylacetyl, C₁-C₆ alkanoyl, or chloroacetyl;

with a suitable base, in an inert solvent or when R⁴ is chloroacetyl,with thiourea.

The process is carried out at temperatures between about 0° C. and about50° C., preferably at about 25° C.

Inert solvents which can be used include, for example, tetrahydrofuran,ethyl acetate, halogenated hydrocarbons such as methylene chloride, di-or tri-chloroethane and the like.

In the above formulae, R₂ is hydrogen, halo, C₁ -C₆ alkoxy, C₁ to C₆alkyl, C₁ to C₆ substituted alkyl C₁ to C₆ alkyltio, C₁ to C₆substituted alkylthio, C₁ to C₁₂ arylalkyl, C₇ to C₁₂ substitutedarylalkyl, phenyl or substituted phenyl; a group of the formula

    --CY.sub.3

wherein Y is fluoro, chloro, bromo, or iodo; a

group of the formula

    --COR.sup.6

wherein R⁶ is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₇to C₁₂ arylalkyl, C₇ to C₁₂ substituted arylalkyl, phenyl, substitutedphenyl, amino, (monosubstituted)amino, or (disubstituted)amino a groupof the formula

    --COOR.sup.7

wherein R⁷ is hydrogen, an organic or inorganic cation, C₁ to C₆ alkyl,C₁ to C₆ substituted alkyl, C₇ to C₁₂ arylalkyl, C₇ to C₁₂ substitutedarylalkyl, phenyl, substituted phenyl, a carboxy-protecting group, or anon-toxic, metabolicallylabile, ester-forming group; a group of theformula --CH₂ --S--"Heterocyclic"; a group of the formula--S--"heterocyclic"; a group of the formula --OR⁹ wherein R⁹ ishydrogen, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₇ to C₁₂arylalkyl, C₇ to C₁₂ substituted arylalkyl, phenyl, substituted phenylor C₁ to C₇ acyl.

A preferred embodiment of this invention is the process wherein A and A'are taken together and form a group of the formula ##STR4##

A preferred embodiment of this invention is the process wherein X is--CH₂ --or sulfur.

An especially preferred embodiment of this invention is the processwherein X is --CH₂ --.

In the above Formulae, the term "C₁ to C₆ alkyl" denotes such radicalsas methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl,amyl, tert-amyl, hexyl and the like. The preferred "C₁ to C₆ alkyl"group is methyl.

The term "C₁ to C₆ substituted alkyl" denotes the above C₁ to C₆ alkylgroups that are substituted by one or two halogen, hydroxy, protectedhydroxy, amino, protected amino, C₁ to C₇ acyloxy, nitro, carboxy,protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylaminoor C₁ to C₄ alkoxy groups. The substituted alkyl groups may besubstituted once or twice with the same or with different substituents.

Examples of the above substituted alkyl groups include the cyanomethyl,nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl,aminomethyl, carboxymethyl, allyloxycarbonylmethyl,allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl,ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl,iodomethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl),2-carbamoyloxyethyl and the like. A preferred group of examples withinthe above "C₁ to C₆ substituted alkyl" group includes the substitutedmethyl group, e.g., a methyl group substituted by the same substituentsas the "C₁ to C₆ substituted alkyl" group. Examples of the substitutedmethyl group include groups such as hydroxymethyl, protectedhydroxymethyl, (e.g., tetrahydropyranyloxymethyl), acetoxymethyl,carbamoyloxymethyl, chloromethyl, bromomethyl and iodomethyl.

The term "C₁ to C₄ alkoxy" as used herein denotes groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and likegroups. The term "C₁ to C₇ acyloxy" denotes herein groups such asformyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy,heptanoyloxy, and the like. Similarly, the term "C₁ to C₇ acyl"encompasses groups such as formyl, acetyl, propionyl, butyryl,pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.

The term "substituted phenyl" specifies a phenyl group substituted withone or two moieties chosen from the group consisting of halogen,hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ to C₄alkoxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl,protected aminomethyl, trifluoromethyl or N-(methylsulfonylamino).

Examples of the term "substituted phenyl" include a mono- ordi(halo)phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl and the like; a mono- or di-(hydroxy)phenyl group such as4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, theprotected-hydroxy derivatives thereof and the like; a nitrophenyl groupsuch as 3- or 4-nitrophenyl; a cyanophenyl group, for example,4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono-or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl,4-methoxyphenyl, 3-ethoxyphenyl, 4-(iso-propoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such as 4-carboxyphenyl or 2,4-di(protectedcarboxy)phenyl; a mono- or di(hydroxymethyl)phenyl or (protectedhydroxymethyl)phenyl such as 3-(protected hydroxymethyl-)phenyl or3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or(protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or2,4-(protected aminomethyl)phenyl; or a mono- ordi(N-(methylsulfonylamino))phenyl such as3-(N-(methylsulfonylamino))phenyl. Also, the term "substituted phenyl"represents disubstituted phenyl groups wherein the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenylgroups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl,the 2-aminomethylphenyl and the 3-(N-(methylsulfonylamino))phenylgroups.

When the various groups which comprise the R₂ definition include anamino and/or hydroxy moiety, it is desirable that said amino and/orhydroxy moiety will be suitably protected using methodology known per sein the art in order to prevent unwanted O- or N-acylation.

The terms "halo" and "halogen" refer to the fluoro, chloro, bromo oriodo groups. Chloro is preferred.

The term "trihalomethyl" denotes trifluoromethyl, trichloromethyl,tribromomethyl or triiodomethyl.

The terms C₁ to C₆ alkylthio and C₁ to C₆ substituted alkylthio denoteC₁ to C₆ alkyl and C₁ to C₆ substituted alkyl groups, respectively,attached to a sulfur which is in turn the point of attachment for the C₁to C₆ alkylthio or C₁ to C₆ substituted alkylthio group.

The term "C₇ to C₁₂ arylalkyl" denotes a C₁ to C₆ alkyl groupsubstituted at any position by a phenyl ring. Examples of such a groupinclude phenyl methyl (benzyl), 2-phenylethyl, 3-phenyl-(n-propyl),4-phenylhexyl, 3-phenyl-(n-amyl), 3-phenyl-(sec-butyl), and the like. Apreferred group is the benzyl group.

The term "C₇ to C₁₂ substituted arylakyl" denotes a C₇ to C₁₂ arylalkylgroup substituted on the C₁ to C₆ alkyl portion with one or two groupschosen from halogen, hydroxy, protected hydroxy, amino, protected amino,C₁ to C₇ acyloxy, nitro, carboxy, protected carboxy, carbamoyl,carbamoyloxy, cyano, C₁ to C₆ alkylthio, N-(methylsulfonylamino) or C₁to C₄ alkoxy; and/or the phenyl group may be substituted with 1 or 2groups chosen from halogen, hydroxy, protected hydroxy, nitro, C₁ to C₆alkyl, C₁ to C₄ alkoxy, carboxy, protected carboxy, carboxymethyl,protected carboxymethyl, hydroxymethyl, protected hydroxymethyl,aminomethyl, protected aminomethyl, or an N-(methylsulfonylamino) group.As before, when either the C₁ to C₆ alkyl portion or the phenyl portionor both are disubstituted, the substituents can be the same ordifferent.

Examples of the term "C₇ to C₁₂ substituted arylalkyl" include groupssuch as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl,2,6-dihydroxy-4-phenyl(n-hexyl), 5-cyano-3-methoxy-2-phenyl(n-pentyl),3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl,6-(4-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethylphenyl)-3-(aminomethyl)(n-pentyl), and the like.

The term "(monosubstituted)amino" refers to an amino group with onesubstitutent chosen from the group consisting of phenyl, substitutedphenyl, C₁ to C₆ alkyl, and C₇ to C₁₂ arylalkyl, wherein the latterthree substituent terms are as defined above.

The term "(disubstituted)amino" refers to amino groups with twosubstituents chosen from the group consisting of phenyl, substitutedphenyl, C₁ to C₆ alkyl, and C₇ to C₁₂ arylalkyl wherein the latter threesubstituent terms are as described above. The two substituents can bethe same or different.

The term "carboxy-protecting group" as used herein refers to one of theester derivatives of the carboxylic acid group commonly employed toblock or protect the carboxylic acid group while reactions are carriedout on other functional groups on the compound. Examples of suchcarboxylic acid protecting groups include 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl,2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl,4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4', 4"-trimethoxytrityl,2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl,2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl,β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The speciesof carboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the condition of subsequentreaction(s) on other positions of the β-lactam molecule and can beremoved at the appropriate point without disrupting the remainder of themolecule. In particular, it is important not to subject thecarboxy-protected β-lactam molecule to strong nucleophilic bases orreductive conditions employing highly activated metal catalysts such asRaney nickel. (Such harsh removal conditions are also to be avoided whenremoving amino-protecting groups and hydroxy-protecting groups,discussed below.) Preferred carboxylic acid protecting groups are theallyl and p-nitrobenzyl groups. Similar carboxy-protecting groups usedin the cephalosporin, penicillin and peptide arts can also be used toprotect a carboxy group substituents of the β -lactam. Further examplesof these groups are found in E. Haslam, "Protective Groups in OrganicChemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973,Chapter 5, and T. W. Greene, "Protective Groups in Organic Synthesis",John Wiley and Sons, New York, N.Y., 1981, Chapter 5. A related term is"protected carboxy", which refers to a carboxy group substituted withone of the above carboxy-protecting groups.

The term "heterocyclic" denotes optionally substituted 5-membered or6-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfurand/or nitrogen, in particular nitrogen, either alone or in conjunctionwith sulfur or oxygen ring atoms. These 5-membered or 6-membered ringsmay be fully unsaturated or partially unsaturated, with fullyunsaturated rings being preferred.

Furthermore, the above optionally substituted 5-membered or 6-memberedrings can optionally be fused to an aromatic 5-membered or 6-memberedring system. For example, the rings can be optionally fused to anaromatic 5-membered or 6-membered ring system such as a pyridine or atriazole system, and preferably to a benzene ring.

The following ring systems are examples of the heterocyclic (whethersubstituted or unsubstituted) radicals denoted by the term"heterocyclic": thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzthiazolyl, benzimidazolyl and indolyl

Preferred heterocyclic rings are 5-membered ring systems containing asulfur or oxygen atom and one to three nitrogen atoms. Examples of suchpreferred groups include thiazolyl, in particular thiazol-2-yl andthiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yland 1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, andoxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Agroup of further preferred examples of 5-membered ring systems with 2 to4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl;triazolyl, preferably 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl,1,2,4-triazol-5-yl, and tetrazolyl, preferably 1H-tetrazol-5-yl. Apreferred group of examples of benzo-fused derivatives are, inparticular, benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.

Further specific examples of the above heterocyclic ring systems are6-membered ring systems containing one to three nitrogen atoms. Suchexamples include pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl;pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl,preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, inparticular pyridazin-3-yl, nd pyrazinyl. The pyridine N-oxides andpyridazine N-oxides, and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,pyridazinyl and the 1,3,4-triazin-2-yl radicals, are a preferred group.

The substituents for the optionally substituted heterocyclic ringsystems, and further examples of the 5- and 6- membered ring systemsdiscussed above, are found in W. Durckheimer et al., U.S. Pat. No.4,278,793, issued Jul. 14, 1981, columns 9 through 21 and columns 33through 188, herein incorporated by reference. (In columns 33 through188, examples of the term "heterocyclic" are included in theheterocyclic thiomethyl groups listed under heading "A".)

A particularly preferred group of "heterocyclics" is 1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl,2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-ylsodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl-1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl,2-thiol-1,3,4-thiadiazol-5-yl, 2-(methylthio)-1,3,4-thiadiazol-5-yl,2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonicacid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1 H-tetrazol-5-yl sodiumsalt, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl,1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl,4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide,6-methoxy-2-(N-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-as-triazin-3-yl,2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,tetrazolo-[1,5-b]pyridazin-6-yl and8-aminotetrazolo[1,5-b]-pyridazin-6-yl.

A most preferred group of "heterocyclics" is4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)-eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl, and8-aminotetrazolo-[1,5-b]pyridazin-6-yl.

As used herein, the term "amide-protecting group" refers to any grouptypically used in the β-lactam art for protecting the β-lactam ringnitrogen from undesirable side reactions. Such groups includep-methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl,di-(p-methoxyphenyl)methyl, triphenylmethyl,(p-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl,m-2-(picolyl)-N'-oxide, 5-dibenzosuberyl, trimethylsilyl, t-butyldimethylsilyl, and the like. Further descriptions of the utility ofthese protecting groups can be found in "Protective Groups in OrganicSynthesis", by Theodora W. Greene, 1981, John Wiley & Sons, New York.

The term "suitable base" refers to primary or secondary amines or analkali metal hydroxide. Such suitable bases which can be used asselective nucleophiles include C₁ -C₇ primary and C₂ -C₁₄ secondaryamines such as methylamine, ethylamine, propylamine, butylamine,pentylamine, hexylamine, heptylamine, dimethylamine, diethylamine,dipropylamine, dibutylamine, dipentylamine, dihexylamine, diheptyl,methylethylamine, methylpropylamine, methylbutylamine,methylpentylamine, methylhexylamine, methylheptylamine,ethylpropylamine, ethylbutylamine, ethylpentylamine, ethylhexylamine,ethylheptylamine, propylbutylamine, propylpentylamine, propylhexylamine,propylheptylamine, benzylamine, and the like. Further examples ofsecondary amines include tetrahydropyrazole, piperidine, and the like.Also included are the diamines such as N,N-diethylethylenediamine, andthe like.

Preferred "suitable bases" include lithium hydroxide andN,N-diethylethylene diamine.

In the process provided by this invention, an acylamino-substitutedβ-lactam is first acylated to provide a diacylamino-substituted β-lactamwhich is then treated with a suitable base to provide the protectedamino monosubstituted β-lactam represented by Formula (1) in which theoriginal acyl substituent has been interchanged for a different and moredynamic protecting group.

For example, a compound of the formula ##STR5## is acylated withdi-t-butyldicarbonate in the presence of base to provide a compound ofthe formula ##STR6##

This imide can then be treated with a suitable base, for example,N,N-diethylehhylene diamine, to provide a compound of the formula##STR7##

Accordingly, the phenoxyacetyl group or any other of several acetyl orsubstituted acetyl groups can be removed in a facile manner by firstsynthesizing the imide of Formula (2) followed by reaction with asuitable base.

Further, when the amide substitutent (R) is chloroacetyl, the resultingimide (2) can be treated with thiourea to provide the desired protectedamino substituted β-lactam (1).

Temperature for formation of the imide should not be so high as to causedecomposition of the β-lactam substrate, but is not otherwise critical,so long as sufficient heat is present for the acylation to occur. It ispreferable that the temperature be between about 0° C. and about 80° C.

The presence of a base is also desirable for the formation of the imidevia deprotonation of the amino β-lactam. Such bases which are usedtypically include potassium hydroxide, sodium hydroxide andtriethylamine. Choice of a base in this context is also dictated by therelative reactivity of the β-lactam substrate to undesired nucleophilicside reactions.

The original β-lactam amide substituent is typically an acyl group suchas phenoxyacetyl, phenylacetyl, chloroacetyl or any such substituted orunsubstituted acetyl group. As such, removal of the original aminosubstituent using known procedures may, at times, either not work atall, or work, but at the same time be deleterious to other reactivesites on the β-lactam substrate.

Thus, it would be desirable if one of the above acetyl or substitutedacetyl groups can be removed in a facile manner, while retaining theintegrity of the β-lactam substrate.

In the present invention, it is preferred that the original substitutedamino-β-lactam be acylated with a compound of the formula (R)₂ O or R-L,in the presence of a base, wherein L is a suitable leaving group Typicalleaving groups (L) include bromo, iodo, chloro, imidazole, and the like.Although many acylating agents of the formula (R)₂ O or R-L would beefficacious, di-t-butyldicarbonate is preferred.

The imide can then be treated with a suitable base, as described herein,to provide a compound of Formula (1). This displacement can be carriedout in many polar organic solvents such as tetrahydrofuran, CH₂ Cl₂,ethanol, propanol, butanol, dichloroethane, dioxane, ethyl acetate, andthe like. Preferred solvents are tetrahydrofuran and CH₂ Cl₂.

After a relatively short reaction time, typically 5 minutes to 2 hours,the desired product can be isolated by conventional methods and purifiedby chromatography over silica gel, if necessary.

The result of the process of this invention is thus an amino-substitutedβ-lactam substrate which is protected on the amino nitrogen with a moredynamic protecting group. For example, if R=t-butoxycarbonyl, one needonly treat the β-lactam substrate with an acid such as trifluoroaceticacid followed by treatment with base to provide the freeamino-substituted β-lactam in good yield. The process of this inventionoffers yet another solution to the problem of manipulation of protectinggroups on the relatively sensitive amino-substituted β-lactam system andthus aids in the synthesis of clinically useful β-lactam antibiotics.

As one aspect of this invention, when X is sulfur, the resulting productmay sometimes contain a mixture of Δ² and Δ³ isomers. This problem maybe overcome by simply employing the the procedure outlined by G. V.Kaiser, et al., J. Org. Chem., 35, 2430 (1970). See also,"Cephalosporins and Penicillins" edited by Edwin H. Flynn, pp. 144-151,Academic Press(1972). According to this well-known method, a Δ² cephemcan be oxidized to its corresponding sulfoxide, and in the process, thecephem bond is isomerized back to the Δ³ isomer.

Thus, as a further aspect of this invention, there are provided novelintermediates of Formula (2), ##STR8## wherein R, R⁴, A and A' are asdefined above.

The class of suitable β-lactam substrates as defined in Formula (2) arerather numerous, the only limitation being stability under therelatively mild reaction conditions of the present invention.

Typical examples of β-lactam substrates include, but are not limited to,the monobactams, cephalosporins, oxacephalosporins such as moxalactam,and 1-carba(dethia)cephalosporins.

The monobactams, cephalosporins, and oxacephalosporins have been broadlydisclosed and the necessary syntheses are known to one skilled in theβ-lactam art. The 1-carba(dethia)cephalosporins have also beendisclosed, but perhaps to a lesser degree. Thus, the synthesis of aparticular class of 1-carba(dethia)-cephalosporins is described below.(For a more complete description, see copending application, U.S. Ser.No. 066,908.)

Examples of one class of the 1-carbacephalosporins which are viablesubstrates for the process of this invention can be prepared by reactinga 3β-protected amino-4β-(2-substituted-ethyl)azetidin-2-one representedby Formula (AA): ##STR9## wherein R^(o) represents an amino groupsubstituted by a conventional amino-protecting group such as R or R⁴above, and T is a leaving group such as bromo, iodo, methanesulfonyloxy,trifluoromethylsulfonyloxy, or p-toluenesulfonyloxy, with aphenylsulfinyl or phenylsulfonyl substituted acrylic acid esterrepresented by Formula (BB): ##STR10## wherein A" is hydrogen, amino, C₁to C₆ alkyl, C₁ to C₆ substituted alkyl, C₇ to C₁₂ arylalkyl, C₇ to C₁₂sustituted arylalkyl, phenyl or substituted phenyl, k is 1 or 2, and R¹is as defined above, to provide a 7β-protected amino-1-carba-3-cephemester represented by Formula (3): ##STR11##

The condensation of (AA) with (BB) is preferably carried out in an inertaprotic solvent under substantially anhydrous conditions at atemperature between about -90° C. and about -45° C. with a strongnon-nucleophilic base.

Inert aprotic solvents which can be used are aprotic organic solvents,for example, tetrahydrofuran, tetrahydropyran, dioxane, acetonitrile,diethyl ether, dimethylformamide, dimethylacetamide,1,2-dimethoxyethane, and like solvents. Mixtures of such solvents may beused.

Non-nucleophilic bases which can be used include the silylated lithiumamides such as bis(tri-C₁ -₄ alkylsilyl)lithium amides, e.g.,bis-(trimethylsilyl)lithium amide, lithium diisopropylamide (LDA),sodium or potassium hexamethyldisilazide, and like bases.

For best results, the base, the acrylic acid ester (BB), and the4-(2-substituted-ethyl)azetidinone (AA) are used in about equimolaramounts.

The process is carried out by first adding the non-nucleophilic base toa cold solution of (AA), in an inert solvent. The solution is stirred inthe cold for a time sufficient to allow generation of the anion formedwith the base and the azetidinone nitrogen. Generally, the mixture isstirred in the cold for about 20 minutes to about one hour. Next, thephenylsulfinyl acrylic acid ester, (BB), or a solution thereof in aninert aprotic solvent is added to the cold basic solution. The reactionmixture is stirred for a short time in the cold and then is allowed towarm slowly to room temperature. Prior to warming, the addition of asmall amount of DMPU (approximately 20 mole percent)(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone) to the reactionmixture appears to enhance the yield of the product. Stirring iscontinued for about 30 minutes to about one hour after the mixture haswarmed to room temperature to complete the condensation.

The 7β-protected amino-1-carba-3-cephem ester, (2), is recovered fromthe reaction mixture by extraction into a water immiscible organicsolvent The solution is evaporated and the reaction product mixturedissolved in toluene, a higher boiling glycol ether, chlorobenzene orother inert solvent having a suitable boiling point, and heated at atemperature above about 85° C., preferably above 100° C., for about 15minutes to about 4 hours to complete the elimination of thephenylsulfinic acid residue, or the phenylsulfonic acid residue. Thesolvent is removed and the product is purified by chromatography over asuitable adsorbent such as silica gel. When the process is carried outon a small scale, the product may be purified by HPLC or by preparativethick layer chromatography.

The 7β-protected amino-1-carba-3-cephem ester product (2) can then bedeprotected and reacylated with a desired carboxylic acid or an activederivative thereof, to provide a 1-carba(dethia)cephalosporinantibiotic.

The amino-protected-azetidin-2-one (AA) utilized in the preparation ofthese 1-carba(dethia)cephalosporin substrates, is prepared as shownbelow in Scheme 1 by the cycloaddition of the imine (formed withbenzylamine and 3-t-butyldimethylsilyloxy)propionaldehyde) with thechiral auxiliary 4(S)-phenyl-1,3-oxazolidin-2-one-3-ylacetyl chloride(step 1). (For a description of the preparation of this chiralauxiliary, see Evans and Sjogren, Tetrahedron Letters, Vol. 26, No. 32,pp. 3783-3786, 1985.) The imine is formed in dry toluene in the presenceof a drying agent such as molecular sieves or via azeotropicdistillation of water. The chiral oxazolidinone acetyl chloride then isallowed to react with the previously prepared imine in methylenechloride at a temperature between about -80° C. and about -15° C. in thepresence of a tertiary amine such as triethylamine. The cycloadditionproduct (a),N-benzyl-3β-[(4S)-phenyl-1,3-oxazolidin-2-one-3-yl]-4β-(2-t-butyldimethylsilyloxyethyl)azetidin-2-one,is reduced with lithium in ammonia containing t-butyl alcohol (step 2)to remove the chiral auxiliary and the N-benzyl group to provide (b) the3β-amino-4β-(2-t-butyldimethylsilyloxyethyl)azetidin-2-one. The β-aminogroup is protected (step 3) with a suitable conventionalamino-protecting group such as the t-butyloxycarbonyl group (tBOC). Theamino-protected azetidinone (c) is reacted (step 4) in an inert solventat a temperature of about 0° C. to about room temperature withtetra(n-butyl)ammonium fluoride to cleave the silyl ether and form3β-protected amino-4β-(2-hydroxyethyl)-azetidin-2-one (d). The hydroxygroup is converted in step 5 to the mesylate, triflate, or tosylateester (e) with methanesulfonyl chloride, trifluoromethylsulfonylchloride, or tosyl chloride in the presence of a tertiary amine such astriethylamine or pyridine. In step 6 the ester is reacted in acetone atroom temperature with sodium iodide or sodium bromide to form the4-(2-haloethyl)azetidin-2-one (AA) (T=Cl or Br). Preferably the4-(2-iodoethyl)azetidinone is employed in the process for preparingcompounds represented by Formula (2). ##STR12##

In Scheme 1, φ is phenyl; R^(o) is R or R⁴ substituted amino; and##STR13## is t-butyldimethylsilyl.

The phenylsulfinyl-substituted or phenylsulfonyl-substituted acrylicacid ester represented by the foregoing Formula (BB) is prepared asshown below in Scheme 2.

In general, an ester of phenylmercaptoacetic acid or aphenylthiomethylketone is alkylated (step 1) with a haloacetic acidester to form a 3-phenylthio-3-substituted propionic acid ester (aa).Chlorination (step 2) of (aa) with N-chlorosuccinimide in carbontetrachloride-THF at the reflux temperature provides the3-chloro-3-phenylthio-3-substituted propionic acid ester (bb).

Dehydrohalogenation (step 3) of (bb) with a strong non-nucleophilic basesuch as DBU forms the 3-phenylthio-3-substituted acrylic acid ester (cc)as a mixture of the two geometric isomers. For purposes of preparing the1-carba-3-cephem compounds of the formula 1, the mixture need not beseparated into the individual isomers.

In step 4 the phenylthio group of (cc) is oxidized in methylene chlorideat room temperature or below with a peracid such as peracetic acid toprovide (BB).

The oxidation can be carried out in an inert organic solvent such asmethylene chloride. Peracetic acid is best used in preparing thephenylsulfinyl intermediates (Formula (BB), k=1) whereasm-chloroperbenzoic acid can be used to prepare the phenylsulfonylintermediates (BB) wherein k is 2.

The phenylsulfinyl-substituted intermediates represented by Formula (BB)wherein k is 1 are preferred intermediates in the preparation of1-carbacephalosporins. ##STR14##

In Scheme 2, φ--is phenyl; X is chloro, bromo, or iodo; and A" istypically a group that is inert in the reaction steps outlined in Scheme2, e.g., groups that will undergo mild peracid oxidation, chlorinationwith a positive chlorination reagent such as N-chlorosuccinimide, orthat are incompatible in the alkylation or dehydrohalogenation steps.

In an example of the preparation of the 3-substituted acrylate (BB) viaScheme 2, methyl phenylmercaptoacetate is alkylated with t-butylbromoacetate to form t-butyl 3-phenylthio-3-methoxycarbonylpropionate.The diester is chlorinated with N-chlorosuccinimide and the chloroproduct is reacted with the base DBU to form the unsaturated diesterrepresented by the formula ##STR15## Oxidation of the diester withperacetic acid yields the corresponding phenylsulfinyl ester representedby the above Formula (BB) wherein A" is methoxy and R¹ is t-butyl.

The diester described above is a versatile intermediate which can beconverted to a variety of other intermediates represented by (BB). Thus,the t-butyl group can be selectively removed with trifluoroacetic acid(TFA) in the cold to form the mono ester and the free carboxy groupre-esterified to form a different mixed diester. For example, the mixedmethyl t-butyl diester of the above formula is treated with TFA to formthe mono ester of the formula ##STR16## The monoester is then esterifiedwith the desired ester forming group to form a different mixed diester.For example, the free acid is esterified with allyl bromide in thepresence of triethylamine to form the mixed methyl allyl diesterrepresented by the formula ##STR17##

The methyl ester group of the above mixed methyl t-butyl diester sulfidelikewise can be selectively deesterified to the mono t-butyl ester andthe free carboxy group reesterified to a different mixed diester.Alternatively, the free carboxy group can be converted to anothercarboxy derivative represented by (A), e.g., an amide, and then used inthe cyclization reaction with the intermediate of Formula (AA) to formthe corresponding 1-carba-3-cephem represented by Formula (3) wherein R¹is the carboxy-protecting group R¹ of (BB). Accordingly, the mixedmethyl t-butyl diester represented by the formula ##STR18## prepared viasteps 1 through 3 of Scheme 2 is treated in THF with an equimolar amountof lithium hydroxide to form the mono t-butyl ester represented by theformula ##STR19## The carboxy group can be reesterified with the desiredester forming reagent or converted to another carboxy derivative such asan acid halide, azide, or amide. Following the reesterification orconversion to a carboxy derivative, the product is oxidized with aperacid to the corresponding phenylsulfinyl or phenylsulfonyl derivative(BB).

In another example of the preparation of a3-phenylsulfinyl-3-substituted-acrylate (BB), the ketone,phenylthioacetone is alkylated in THF with t-butyl bromoacetate andsodium hydride to yield t-butyl 3-phenylthio-4-oxopentanoate. The ketoester is chlorinated in THF with N-chlorosuccinimide to the 3-chloroketo ester and the latter dehydrohalogenated to t-butyl3-phenylthio-4-oxopent-2-eneoate. The unsaturated keto ester is thenoxidized in methylene chloride with peracetic acid to (BB) wherein A" ismethyl and R¹ is t-butyl as represented by the following formula##STR20##

Examples of substituted acrylate esters represented by Formula (BB)which can be obtained by the above-described methods are shown in thefollowing Table 1.

                  TABLE I                                                         ______________________________________                                         ##STR21##                                                                    A"                    R.sup.1                                                 ______________________________________                                        C.sub.2 H.sub.5       t-butyl                                                 OCH.sub.3             t-butyl                                                 OCH.sub.3             benzhydryl                                              CH.sub.2 C.sub.6 H.sub.5                                                                            t-butyl                                                 OCH(CH.sub.3).sub.2   pNB.sup.2                                               C.sub.6 H.sub.5       pMB.sup.1                                               NH.sub.2              C.sub.2 H.sub.5                                         OH                    CH.sub.3                                                N(CH.sub.3).sub.2     (CH.sub.3).sub.3 Si                                     NHC.sub.2 H.sub.5     benzyl                                                  C.sub.4 H.sub.9       (CH.sub.3).sub.3 Si                                     CH.sub.3              benzyl                                                  ______________________________________                                         .sup.1 p-methoxybenzyl                                                        .sup.2 p-nitrobenzyl                                                     

the amino-protected 1-carbacephalosporin represented by Formula (3)above can be substituted, deblocked, and N-acylated to provide other1-carba(dethia)cephalosporins.

For example, a 7β-amino-protected-3-acetyl-1-carba-3-cephem esterrepresented by the formula ##STR22## wherein R^(o) and R¹ have theabove-defined meanings, which is prepared with intermediate (BB) whereinA" is methyl, is reacted with bromine in the presence of a stronnon-nucleophilic base such as LDA (lithium diisopropyl amide) to formthe 3-bromoacetyl derivative represented by the formula ##STR23## The3-bromoacetyl ester is reacted with an O, S, or N nucleophile to providea 3β-protected amino 1-carba-3-cephem ester and the latter isdeprotected and N-acylated to a compound of Formula (1). For example,the 3-bromoacetyl ester can be reacted with a 5- or 6-membered nitrogencontaining heterocyclic thiol or an alkali metal salt thereof to formthe compound wherein R² is the group ##STR24## "Heterocyclic". Thissequence is further illustrated by the following scheme. ##STR25##

Accordingly, when R² is CH₃, the same sequence can be performed toprovide R² =--CH₂ --S--"Heterocyclic".

In the Examples and Preparations, the following abbreviations have theindicated meanings: BSTFA=bis(trimethylsilyl)trifluoroacetamide;DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene; DMF=dimethylformamide; HPLC=highperformance liquid chromatography; t-BOC=t-butyloxycarbonyl;THF=tetrahydrofuran; NMR=Nuclear Magnetic Resonance (H¹ spectrum); andJ=coupling constant for NMR spectra in Hz.

EXAMPLE 1 p-Nitrobenzyl7β-[(N-phenoxyacetyl-N-(t-butyloxycarbonyl)amino]-3-methyl-3-cephem-4-carboxylate

A solution ofp-nitrobenzyl-3-methyl-7β-phenoxyacetylamino-3-cephem-4-carboxylate(0.4-3 g, 1.89 mM, 2.0 equivalents), di-t-butyldicarbonate (0.116 g)4-dimethylaminopyridine, and (0.13 ml) triethylamine in 20 ml of CH₂ Cl₂was stirred at room temperature for 1 hr. The reaction mixture was thenextracted sequentially with cold 1N HCl, brine, and dried over anhydroussodium sulfate. Removal of the CH₂ Cl₂ in vacuo followed by silica gelchromatography (toluene/ethyl acetate gradient elution) provided 335 mg(60% yield) of the title compound.

Mass Spectra: m/e 583; IR (CHCl₂) 1765 cm⁻¹ (β-lactam), nmr (CDCl₃) δ:1.56 (s, 9, t-Bu), 2.24 (s, 3 Me), 3.2, 3.4 (AB, J=16 Hz, 2, C(2)protons - H⁷ to H² β[5-bond]coupling, 5.06 (d, J=4 Hz, 1, H⁶), 5.21 (s,2, PhOCH₂), 5.31, 5.44 (AB, J=13 Hz, 2, PNB), 5.83 bd, J=4 Hz, 1, H⁷).

In a procedure analogous to that in Example 1, the following compoundswere prepared.

EXAMPLE 2 Methyl 3-methyl-7β-[(N-phenylacetyl,N-t-butoxycarbonyl)amino]-3-cephem-4-carboxylate

NMR (60 MHz, CDCl₃): δ: 1.50 (s, 9H, t-Bu); 2.15 (s, 3H, 3-methyl); 3.17(m, 2H, C-2 protons); 3.83 (s, 3, CO₂ CH₃); 4.25 (s, 2H, φCH₂ ; 4.93 (d,J=4 Hz, 1H, H⁶): 5.73 (d, J=4 Hz, 1, H⁷).

EXAMPLE 3 Methyl 3-methyl-7β-[(N-acetyl,N-t-butoxycarbonyl)amino]-3-cephem-4-carboxylate

IR (CHCl₃) 1775 cm⁻¹ (β-lactam carbonyl)

FDMS: 370 m/e

NMR (60 MHz, CDCl₃) δ: 1.63 (s, 9H, t-Bu); 2.32 (s, 3, 3--CH₃); 2.67 (s,3H, acetyl); 3.29, 3.58 (AB, J=16 Hz, 2H, C-2 protons); 3.97 (s, 3, CO₂CH₃); 5.10 (d, J=4 Hz, 1H, H⁶); 5.87 (d, J =4 Hz, 1, H⁷).

EXAMPLE 4 p-Nitrobenzyl 3-methyl-7β-[(N-chloroacetyl,N-butoxycarbonyl)amino-3-cephem-4-carboxylate

IR (CHCl₃) 1780 cm⁻¹ (β-lactam carbonyl)

FDMS: 529 m/e

NMR (300 MHz, CDCl₃) δ: 1.51 (s, 9H, t-Bu); 2.22 (s, 3H, CH₃); 3.23,3.45 (AB, J=16 Hz, 2H, C-2 protons 4.73 (s, 2H, CH₂ -Cl); 5.04 (d, J=4Hz, 1H, H⁶); 5.29, 5.41 (AB, J=13 Hz, 2H, P-NO₂ -φ-CH₂ -); 5.77 (d, J=4Hz, 1H, H⁷).

EXAMPLE 5 p-Nitrobenzyl3-methyl-7β-[(N-methoxyacetyl,N-t-butoxycarbonyl)amino]-3-cephem-4-carboxylate

IR (CHCl₃) 1770 cm⁻¹ (β-lactam carbonyl)

FDMS: 507 m/e

NMR (300 MHz, CDCl₃) (Δ³ isomer only); 1.52 (s, 9H, t-Bu); 2.28 (s, 3H,CH₃) ; 3.16, 3.57 (AB, J=16 Hz, 2H, C-2 protons) ; 3.87 (s, 3H, --OCH₃);5.05 (d, J=4 Hz, 1H, H⁶); 5.28, 5.44 (AB, J=13 Hz, 2H, p-NO₂ φ-CH₂ --);5.64 (d, J=4 Hz, 1H, H⁷).

EXAMPLE 6 Benzhydryl 3-acetoxymethyl-7β-[(N-formyl,N-t-butoxycarbonyl)amino]-2-cephem-4-carboxylate

FDMS: 566 m/e

NMR (60 MHz, CDCl₃ (on Δ² only): 1.57 (s, 9H, t-Bu); 2.00 (s, 3H, CH₃);4.68 (s, 2, --CH₂ --O--acetyl); 5.16 (broad s, 1H, C-4); 5.25 d, J=4 Hz,1H, H⁶); 5.67 (d, J=4 Hz, 1H, H-7); 9.23 (s, 1H, HC(O)).

EXAMPLE 7 2,2,2-Trichloroethyl 3-Methyl-7β-(N-allyloxycarbonyl,N-t-butoxycarbonyl)amino-3(2)-cephem-4-carboxylate

IR (CHCl₃) 1750-1780 cm⁻¹ (broad) (β-lactam carbonyl)

FDMS: 528, 530 m/e

NMR (300 MHz, CDCl₃) Δ² /Δ³ mixture δ: 1.6 (s, t-Bu); 2.0 (s, 3H, CH₃);3.1, 3.6 (AB, 5H, J=16 Hz, H² protons); 5.1, 5.3, 5.9 (m, allylprotons); 5.6 (d, J=4 Hz, H⁶); 5.7 (d, 1H, J=4 Hz, H⁷); 6.0 (s, 1H, H²of Δ² isomer).

EXAMPLE 8 p-Nitrobenzyl, 3-methyl-7δ-[(methoxycarbonyl,butoxycarbonyl)amino]-3-cephem-4-carboxylate

Mass spectrum 507 (m/e)

IR 1770 cm⁻¹ (β-lactam carbonyl)

NMR (300 MHz CDCl₃ 1.52 (s, 9H, t-Bu); 2.28 (s, 3H, CH₃ --); 3.16, 3.57(AB, J =16 Hz, 2H, c(2)-protons); 5.05 (d, J =4 Hz, 1H, H⁶); 5.28, 5.44(AB, J =13 Hz, 2H, p-NO₂ --φ--CH₂ --); 5.64 (d, J =4 Hz, 1H, H⁷); 7.63,8.24 (AB, J =8.5 Hz, 4H, p-NO₂ --φ--CH₂ --).

EXAMPLE 91-(t-Butyldimethylsilyl)-3β-[(N-phenoxyacetyl-N-t-butyloxycarbonyl)amino]-4-(2-t-butyloxycarbonylthiomethyl)-azetidin-2-one

A) Silylation

The free-N-H compound (0.636 g, 174 mM), 275 mg (182 mM) of t-butyldimethylsilyl chloride and 0.25 ml of triethylamine were dissolved in 10ml of dimethylformamide and allowed to stir at room temperature for 2days. The reaction mixture was then diluted with ethyl acetate andextracted sequentially with H₂ O (4 times), and brine (1 time), anddried over anhydrous sodium sulfate. The crude product was evaporated todryness and used as is in Part B, below.

B) The product from Part A was dissolved in 15 ml of CH₂ Cl₂ and treatedwith 757 mg (347 mM) of di-t-butyldicarbonate, 212 mg (173 mM) ofdimethylamino pyridine, and 0.24 ml of triethylamine. After stirring for1 hour, the reaction mixture was diluted with cold ethyl acetate andwashed sequentially with cold 1N HCl and brine and dried over anhydroussodium sulfate. Chromatography on 15 g of Merck silica gel using agradient elution beginning with 400 ml of toluene and ending with 400 mlof ethyl acetate/toluene (1:1) provided 537 mg (53% overall yield) ofthe title compound.

IR (CHCl₃) 1814 cm⁻¹ (β-lactam carbonyl)

FDMS: 580, 566 m/e

NMR (60 MHz, CDCl₃) δ: 0.37 (s, 3H, Si-CH₃); 1.00 (s, 3H, Si-CH₃); 1.43,1.57 (s, 27H, t-butyl), 3.25, 3.58 (AB, J=14 Hz, 2H, CH₂ --CO₂-t-butyl); 5.23 (m, 2H, --O--CH₂ φ); 5.50 (d, J=4 Hz, 1H, H⁴); 6.08 (d,J=4 Hz, 1H, Hs).

EXAMPLE 10Methyl-3-methyl-7β-(t-butoxycarbonyl)amino-3-cephem-4carboxylate andmethyl-3-methyl-7β-(t-butoxycarbonyl)-amino-2-cephem-4-carboxylatemixture

The product of Example 2 (226 mg) was dissolved in 15 ml of CH₂ Cl₂,cooled to -78° C., and treated with 59 mg of N,N-diethylethylenediamine, utilizing an additional 5 ml of CH₂ Cl₂ as a wash solution toaid quantitative transfer. The reaction mixture was allowed to warm toroom temperature and stirred for 38 hours. The crude product mixture wasthen extracted sequentially with cold 1N HCl and brine, and dried overanhydrous sodium sulfate. The crude product was then chromatographedover 8.0 g of Merck silica using 300 ml of toluene and 300 ml of ethylacetate in a gradient elution to provide the title compound as a mixtureof Δ² +Δ³ isomers (116 mg yield).

IR 1775 cm⁻¹ (β-lactam carbonyl)

3350 cm⁻¹ (N-H)

NMR (60 MHz, CDCl₃) δ: 1.52 (s, t-Bu); 1.92 (s, 3H, Δ² C₃ --CH₃) ; 2.33s, 3H, Δ³ --CH₃); 3.20, 3.53 (AB, J=17 Hz, 2H, C₂ --CH₂ for Δ³); 3.83(s, 3H, CO₂ CH₃ for Δ²); 3.87 (s, 3H, CO₂ CH₃ for Δ³) ; 4.73 (Bs, C₄ -Hfor Δ²); 4.97 (d, J=4 Hz, 2H for Δ³); 5.23 (Bs, 1H, C₇ -H for Δ²); 5.43(Bs, 1H, C₇ H for Δ³); 5.97 (Bs, 1H, C₂ -H for Δ²).

EXAMPLE 11 7β-3-Methyl-7-(t-butoxycarbonyl)amino-3-cephem-4-p-nitrobenzyl carboxylate and7β-3-methyl-7-(t-butoxycarbonyl)amino-2-cephem-4-p-nitrobenzylcarboxylate

Utilizing the product from Example 1 and a procedure analogous to thatof Example 11, the title compound was produced.

71% Δ³ /15% Δ²

IR 1770 cm⁻¹ (β-lactam carbonyl)

3420 cm⁻¹ (N-H)

FDMS: 449 m/e

NMR (300 MHz, CDCl₃) δ[Δ³ isomer]: 1.49 (s, 9H, t-Bu); 2.20 (s, 3H, C₃--CH₃) ; 3.29, 3.58 (AB, J=18 Hz, 2H, C₂ -protons); 4.99 (d, J=4 Hz, 1H,H⁶); 5.3-5.5 (m, 3H, p-NO₂ --C₆ H₄ --CH₂ - and N-H); 5.61 (dd, J=4, 9Hz, H⁷).

The following Preparations 1-7 describe the preparation of1-carba(1-dethia)compounds employed in the process.

Preparation of Substituted Acrylic Acid Esters Preparation 1 1-Methyl4-t-butyl 2-phenylsulfinylmaleic acid diester

To a 2-liter, flame-dried flask flushed with nitrogen and equipped witha dropping funnel and stirrer containing bis(trimethylsilyl)lithiumamide(254.23 mmole) in 200 ml of THF and cooled to -42° C. was added asolution of methyl phenylmercaptoacetate (43.33 g, 254.23 mmole) in 100ml of THF. The solution was stirred in the cold for about 25 minutes andwas transferred via cannula over 30 minutes to another flask containingt-butyl bromoacetate (51.08 g, 261.86 mmole) in 100 ml of THF alsocooled to -42° C. The reaction mixture was stirred over 2.5 hours whilethe flask was allowed to warm to room temperature. The reaction mixturewas poured into 800 ml of a saturated solution of ammonium chloride inwater and 1200 ml of ethyl acetate were added. The organic layer wasseparated and the aqueous layer was extracted once with 300 ml of ethylacetate. The extract was combined with the organic layer, dried overmagnesium sulfate, filtered and evaporated under vacuum to yield 80 g ofthe crude product as a brownish oil. The crude product was purified viapreparative HPLC to yield 60 g (79.7% yield) of the product, 1-methyl4-t-butyl 2-phenylthiosuccinic acid diester.

90 MHz NMR (CDCl₃, δ): 1.4 (s, 9H, t-butyl ester H), 2.9-3.0 (m, 2H, CH₂H), 3.7 (s, 3H, COOCH₃), 3.9 (dd, J=7 and 9, 1H, methine H), 7.5-7.2 (m,5H, phenyl H).

The mixed diester phenylsulfide product obtained above (60 g, 202.43mmole) was dissolved in a mixture of 1000 ml of carbon tetrachloride,500 ml of THF and N-chlorosuccinimide (28.38 g, 212.55 mmole) and themixture was heated at the reflux temperature for about 4 hours. The thinlayer chromatogram run with a small portion of the reaction mixtureshowed one major spot and no starting material. The mixture wasevaporated under vacuum and the residue was treated with hexane. Theinsoluble material was filtered, washed with hexane, the hexane washcombined with the hexane filtrate evaporated under vacuum to yield 67 gof 1-methyl 4-t-butyl 2-chloro-2-phenylthiosuccinic acid diester as anorange oil.

The chloro diester obtained above (67 g, 202.51 mmole) was dissolved in1 liter of methylene chloride and the solution cooled to -78° C. DBU(31.44 g, 206.56 mmole) was added to this cold solution via syringe andthe solution turned dark and thickened. The reaction mixture was allowedto warm to room temperature over 1.5 hours when a thin layerchromatogram of the reaction mixture showed two major spots and nostarting material. The mixture was poured into 1 liter of watercontaining 200 ml of 1N hydrochloric acid and the organic layerseparated. The organic layer was again poured into aqueous HCl asbefore, the organic phase separated, dried over magnesium sulfate,filtered and evaporated under vacuum to yield 60 g of the product as abrownish, oily solid. The crude product was purified via preparativeHPLC to yield 47.7 g of 1-methyl 4-t-butyl 2-phenylthiomaleic aciddiester as a light yellow oil which solidified upon standing in therefrigerator overnight.

90 MHz NMR (CDCl₃) δ, 1.4 and 1.5 (s, 9H, t-butyl H), 3.3 and 3.6 (s,3H, COOCH₃), 5.4 and 6.3 (s, 1H, vinyl H), and 7.2-7.6 (m, 5H, phenylH).

To a solution of the maleic acid diester obtained above (2.32 g, 7.95mmole) in 75 ml of methylene chloride and cooled to -42° C. was addedperacetic acid (1.67 ml, 8.745 mmole) and the mixture was allowed towarm to room temperature. The reaction mixture was stirred at roomtemperature for about one hour and 1.95 g of dimethyl sulfide was added.The mixture was stirred for 30 minutes after addition of the sulfide andwas then poured onto a pad of silica gel (150 g). The pad was washedwith methylene chloride until all remaining starting material hadfiltered. The pad was then flushed with diethyl ether until the desiredproduct had filtered. The ether solution of the product was evaporatedto yield the product as a yellow oil. The oil was treated three timeswith 200 ml-portions of toluene, and after each treatment was evaporatedunder vacuum. There were obtained 1.95 g (79% yield) of the2-phenylsulfinyl maleic acid diester as a yellow oil.

90 MHz NMR (CDCl₃, δ): 1.5 and 1.6 (s, 9H, t-butyl), 3.6 and 3.7 (s, 3H,COOCH₂) , 6.9 and 7.2 (s, 1H, vinyl H) , 7.1 and 7.7 (m, 5H, phenyl H).

Preparation 2 1-Methyl 4-allyl 2-phenylsulfinyl maleic acid diester

The methyl t-butyl phenylsulfinyl maleic acid mixed diester obtained asdescribed by Preparation 1 was treated with 8 ml of trifluoroacetic acidat 0° C. to effect selective removal of the t-butyl ester group. After 5minutes, the reaction mixture was allowed to stir for 2 hours at roomtemperature and was then evaporated under vacuum at 45° C. to yield anoil. The oil was dissolved in the minimum amount of methylene chlorideand the solution was diluted with hexane until cloudy. The productprecipitated as a white solid. The mother liquor was decanted from thesolid product which was washed with a mixture of 20% methylenechloride/hexane. The washings were added to the mother liquor and placedin the refrigerator overnight to obtain a second crop of product. Therewere obtained 2.124 g of first crop product and a second crop of 900 mg(79.6% yield) as dried under vacuum.

The phenylsulfinyl half ester obtained as described above (2.124 g,8.362 mmole) was dissolved in 8 ml of DMF and the solution cooled to 0°C. First, allyl bromide (1.011 g, 8.362 mmole) was added to the solutionfollowed by triethylamine (1.25 ml, 9.0 mmole) and the mixture wasallowed to warm to room temperature. The reaction mixture was stirred atroom temperature for 2.5 hours, a thin layer chromatogram of a smallportion of the reaction mixture indicated that most of the startingmaterial had reacted, and showed a new major spot. The very darkreaction mixture was poured into a mixture of 60 ml of diethyl ether and50 ml of water. The aqueous layer was separated and washed with 40 ml ofdiethyl ether. The ether layers were combined and washed sequentiallytwice with 50 ml-portions of a saturated aqueous sodium bicarbonatesolution, twice with 50 ml-portions of 1N hydrochloric acid and oncewith 50 ml of brine. The washed organic layer was dried over magnesiumsulfate, filtered and evaporated under vacuum to yield the product as ayellow oil. The product was taken up in 50 ml of toluene and evaporatedunder vacuum. The process was repeated to yield 1.934 g (78.6% yield) ofthe title compound, the allyl methyl diester. ##STR26##

Preparation 3 1-Ethyl 4-allyl 2-phenylsulfinyl maleic acid diester

To a solution of 1-methyl 4-t-butyl 2-phenylthio maleic acid diester (5g, 16.99 mmole) in 100 ml of THF was added lithium hydroxide (16.99mmole) and the mixture was stirred for 3 hours at room temperature. Thereaction mixture was poured into a mixture of 150 ml of water and 300 mlof diethyl ether, and the aqueous and organic layers were separated. Theaqueous layer was washed twice with 150 ml-portions of diethyl ether andthe ether wash was combined with the organic layer and evaporated toyield 2.2 g of the starting material, the diester. The aqueous layer wasacidified with 17 ml of 1N hydrochloric acid and extracted twice with200 ml-portions of diethyl ether. The extracts were combined, dried overmagnesium sulfate, filtered and evaporated in vacuum to yield 2.7 g ofthe mono t-butylester, 4-t-butyl 2-phenylthiomaleic acid mono ester, asa yellow oil (57%).

To a solution of the phenylthio half ester obtained as as describedabove (8.0 g, 28.551 mmole) in DMF was added via pipette ethyl iodide(4.9 g, 31.406 mmole) and triethylamine (4.78 ml, 34.261 mmole) and themixture was stirred for one hour at room temperature. The reactionmixture was then heated briefly to a temperature of 65° C. and aftercooling, an additional 2.0 ml of ethyl iodide in 4.0 ml of triethylaminewere added. The mixture was again heated briefly to a temperature ofabout 65° C. and was cooled. The reaction mixture was poured into amixture of 200 ml of diethyl ether in 120 ml of water. The organic layerwas separated from the organic layer which was washed twice with 100ml-portions of a saturated aqueous solution of sodium bicarbonate, twicewith 100 ml of 1N hydrochloric acid and once with 100 ml of brine. Theorganic layer was then dried over magnesium sulfate, filtered andevaporated under vacuum to yield 6.51 g of the phenylthio ethyl t-butyldiester as an oil (74% yield).

90 MHz NMR (CDCl₃, δ): 0.9 and 1.1 (t, J =7, 3H, CO₂ CH₂ CH₃), 1.4 and1.5 (s, 9H, t-butyl), 3.7 and 4.1 (q, J=7, 2H, --CO₂ CH₂ CH₃), 5.4 and6.2 (s, 1H, vinyl H), and 7.2 to 7.6 (m, 5H, phenyl H).

The t-butyl ethyl diester, 6.51 g, was treated at room temperature for30 minutes with 9 ml of trifluoroacetic acid to effect selectdeesterification of the t-butyl ester group and provide 5.1 g of 1-ethyl2-phenylthiomaleic acid monoethyl ester as a yellow oil.

90 MHz NMR (CDCl₃, δ): 0.9 and 1.2 (t, J =7, 3H, CO₂ CH₂ CH₃), 3.7 and4.1 (q, J =7, 2H, CO₂ CH₂ CH₃), 5.4 and 6.2 (s, 1H, vinyl H), 7.1-7.6(m, 5H, phenyl H), J and 8.7 (broad s, 1H, COOH).

The half acid ester obtained as described above (5.1 g, 20.222 mmole)was dissolved in 22 ml of DMF and allyl bromide (3.67 g, 30.333 mmole)was added to the solution followed by triethylamine (4.8 ml, 34.38mmole) and the reaction mixture was allowed to stir for approximately 16hours. .The mixture was poured into a mixture of 100 ml of water and 200ml of diethyl ether and the organic layer separated from the aqueouslayer. The organic layer was washed twice with 100 ml-portions of asaturated aqueous sodium bicarbonate solution, twice with 100ml-portions of 1N hydrochloric acid and once with 100 ml of brine. Thewashed layer was then dried over magnesium sulfate, filtered andevaporated under vacuum to yield 5.5 g (93.2% yield) of 1-ethyl 4-allyl2-phenylthiomaleic acid diester as a yellow oil.

90 MHz NMR (CDCl₃, δ): 0.9 and 1.2 (t, J =7, 3H, --CH₂ CH₃), 3.8 and 4.1(q, J =7, 2H, --CH₂ CH₃), 4.5 and 4.6 (dm, J =5, 2H, --CH₂ --CH═CH₂),5.1-5.4 (m, --CH₂ --CH=CH₂ ##STR27## and 7.2-7.6 (m, 5H, phenyl).

The allyl ethyl diester (5.52 g, 18.891 mmole) prepared as describedabove was dissolved in methylene chloride and the solution cooled to atemperature of about -42° C. To the cold solution was added peraceticacid (5.04 ml, 26.447 mmole) and the mixture was allowed to stir forabout 2.5 hours at room temperature. An additional 2.0 ml of peraceticacid was added and the mixture was stirred at room temperature for anadditional 1.5 hours. Dimethylsulfide (4.85 ml, 66 mmole) was then addedto the mixture which was stirred for an additional 45 minutes. Theunreacted starting material was separated by pouring the reactionmixture directly onto 125 g of silica gel and washing the startingmaterial from the silica with methylene chloride. The silica gel wasthen eluted with diethyl ether until all of the desired sulfoxide hadbeen washed free. The product containing filtrate was concentrated undervacuum to provide the sulfoxide diester as a yellow oil. The oil wasdissolved successively six times in 100 ml-portions of toluene and theevaporated to remove toluene to provide 3.8 g of the sulfoxide diesteras an oil (80% yield).

90 MHz NMR (CDCl₃, δ): 1.1 and 1.2 (t, J =7, 3H, --CH₂ CH₃), 4.0 and 4.1(q, J =7, 2H, --CH₂ CH₃), 4.65 and 4.75 (dm, J =5, 2H, --CH₂ --CH═CH₂),5.1-5 (m, 2H, --CH₂ --CH═CH₂), 5.7-6.2 (m, 1H, --CH₂ --CH=CH₂), 6.9 and7.1 (s, 1H, C=CHCOO), and 7.3-7.9 (m, 5H, phenyl).

Preparation 4 t-Butyl7β-t-butyloxycarbonylamino-3-methoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylate

A. Preparation of 2-(dimethyl-t-butylsilyloxy)propionitrile

To a solution of 2-cyanoethanol (7.0 g, 98.48 mmole) in 75 ml of DMF wasadded dimethyl-t-butylchlorosilane (16.028 g, 106.36 mmole) followed byimidazole (8.17 g, 120 mmole). The reaction mixture was stirred forabout 15 hours and was poured into a mixture of 250 ml of diethyl etherand 200 ml of 1N hydrochloric acid. The ether layer was separated andwashed twice with 150 ml of 1N hydrochloric acid. The organic layer wasseparated, dried over magnesium sulfate, filtered and evaporated undervacuum. The silyl ether product was obtained as an oily residue. Theresidue was diluted with 100 ml of toluene and the solution evaporated.This procedure was repeated three times to provide 17.26 g of2-(dimethyl-t-butylsilyloxy)propionitrile as a colorless liquid (94.7%yield).

90 MHz, NMR (CDCl₃, δ): 0.1 (s, 6H, methyl H), 0.9 (s, 9H, t-but H), 2.9(t, J =6, 2H, CH₂ CN), and 3.8 (t, J =6, 2H, SiO-CH₂).

B. 3-(Dimethyl-t-butylsilyloxy)propionaldehyde

To a solution of 3-(dimethyl-t-butylsilyloxy)propionitrile (6.04 g,32.65 mmole) in 50 ml of THF and cooled to a temperature of 0° C. wasadded with a syringe, di-isobutylaluminum hydride (60 mmole in 60 ml ofTHF) and the mixture was allowed to warm to room temperature. After athin layer chromatogram of the reaction mixture indicated that verylittle reaction had occurred, the reaction mixture was heated to refluxfor a few minutes. The reaction mixture was then cooled to roomtemperature and poured into a stirred mixture of 150 ml of 1M tartaricacid and 200 ml of diethyl ether. Some gas evolution occurred and themixture was transferred to a separatory funnel with diethyl ether. Theether layer was separated, dried with magnesium sulfate, filtered, andevaporated in vacuo. The liquid residue containing some suspended solidswas diluted with hexane, filtered and the precipitate washed withhexane. The filtrate and washings were concentrated in vacuo to provide3.7 g of the silyloxy propionaldehyde as a light yellow liquid (60.3%yield). The NMR spectrum indicated the product to be about 75% pure andcontaminated with some starting material and silanol.

90 MHz, NMR (CDCl₃, δ): 0.2 (s, 6H, methyl H), 0.8 (s, 9H, t-but H), 2.5(dt, J =2.5, 6, 2H, CH₂ CO), 3.9 (t, J =6, 2H), and 9.5 (t, J =2.5, 1H,COH).

C. Imine Formed With Benzylamine and3-(Dimethylt-t-butylsilyloxy)propionaldehyde

To a solution of the silyloxypropionaldehyde prepared as described in B.above (2.5 g, 13.3 mmole) in about 20 ml of toluene were addedbenzylamine (10.64 mmole, 1.16 ml) and about 3-4 g of 4A molecularsieves. The mixture was occasionally swirled gently over 25 minutes toform the imine of the silyloxyaldehyde and benzylamine.

D.N-Benzyl-3β-[(4S)-phenyl-1,3-oxazolidin-2-one-3-yl]-4β-(2-dimethyl-t-butylsilyloxyethyl)azetidin-2-one

To a solution of (4S)-phenyl-1,3-oxazolidin-2-one-3-yl acetic acid (2.2g, 9.95 mmole) in 20 ml of toluene were added 1.45 g (11.44 mmole) ofoxalyl chloride. The yellow solution was stirred for one hour and wasthen evaporated to provide the corresponding acid chloride as a yellowoil. The acid chloride was dissolved in 20 ml of methylene chloride andthe solution was cooled to a temperature of about -78° C. Triethylamine(14.93 mmole, 2.08 ml) was added to the solution of the acid chlorideand the solution was stirred for a few minutes at room temperature. Thesolution of the imine prepared as described above in C. was added to theacid chloride solution via cannula and the reaction mixture was allowedto slowly warm to a temperature of about 15°-20° C. over 2 hours. Thereaction mixture was then poured into a mixture of 30 ml of methylenechloride and 30 ml of 1N hydrochloric acid and the organic layer wasseparated. The organic layer was washed with 40 ml of an aqueoussaturated sodium bicarbonate solution and with 40 ml of water and wasdried over magnesium sulfate, filtered, and evaporated under vacuum. Theazetidinone was obtained as a reddish oil. The oil was chromatographedover 100 g of silica gel using 35% ethyl acetate/hexane for elution. Thedesired fractions were combined and concentrated in vacuo to a lightpink solid. The solid was washed with hexane to remove the color and toyield 1.03 g of the azetidinone as a white solid (21.5% yield).

    [α].sub.D.sup.25 =+79.2°

Mass spectrum: (M⁺) 480; (M⁺ -t-butyl) 423.

IR 1750 cm⁻¹ (β-lactam)

Elemental analysis calculated for C₂₇ H₃₆ N₂ O₄ Si:

    ______________________________________                                               Theory        Found                                                    ______________________________________                                               C, 67.47      C, 67.61                                                        H,  8.55      H,  8.78                                                        N,  5.83      N,  6.03                                                 ______________________________________                                    

90 MHz, NMR (CDCl₃, δ): 0.0+0.25 (2s, 6H, methyl H), 0.8 (s, 9H, t-butH), 1.6 (m, 2H, CH₂ H), 3.5 (t, J =6, 2H, SiOCH₂ H), 3.8 (dt, J =5 and6, 1H, C₄ H), 7.1 to 7.5 (m, 10H, phenyl H).

E.3β-t-Butyloxycarbonylamino-4β-(2-dimethyl-t-butylsilyloxyethyl)azetidin-2-one

To 430 ml of liquid ammonia was added 2.385 g (343.71 mmole) of lithiumwashed with hexane and the mixture was stirred for about 20 minutes todissolve the lithium. A solution of the N-benzylazetidinone prepared asdescribed above in D. in 87 ml of THF containing 8.496 g (114.49 mmole,10.8 ml) of t-butanol was added to the lithium-ammonia solution and themixture was stirred vigorously for 50 minutes. A mixture of methylalcohol-toluene (87 ml, 1:1) was added to the mixture followed by 21.7ml of acetic acid. The ammonia was distilled off and the residue wasacidified to pH 5 by the addition of 45 ml of acetic acid. A mixture ofisopropyl alcohol in chloroform (500 ml, 25%) was added to theconcentrate followed by 300 ml of a saturated aqueous sodium bicarbonatesolution to adjust the pH of the mixture to pH 9. The organic layer wasseparated and the aqueous layer was washed twice with 200 ml of 25%isopropyl alcohol in chloroform. The washes were combined with theorganic layer, dried over magnesium sulfate, filtered, and concentratedin vacuo to yield 9.3 g of crude3β-amino-4β-(2-dimethyl-t-butylsilyl-oxyethyl)azetidin-2-one. The crude3-amino compound was dissolved in 50 ml of methylene chloride and 8.486g (38.88 mmole, 8.486 ml) of di-t-butyl-dicarbonate were added to thesolution. The mixture was allowed to stir overnight and was thenevaporated under vacuum to yield 14.67 g of the3β-t-butyloxycarbonylamino acylation product. The product waschromatographed on 150 g of silica gel using ethyl acetate/hexane, 50/50for elution. The fractions containing the desired product were combinedand evaporated in vacuo to yield 11.88 g of3β-t-butyloxycarbonylamino-4-(2-dimethyl-t-butylsilyloxyethyl)azetidin-2-one.

90 MHz, NMR (CDCl₃, δ): 0.0 (s, 6H, methyl H), 0.8 (s, 9H, t-but H), 1.4(s, 9H, t-butyloxy H), 1.7 (m, 2H, CH₂ H), 3.6 (t, J =5, 2H, CH₂ H), 3.9(m, 1H, C₄ H), 5.0 (dd, J =5 and 9, 1H, C₃ H), 5.5 (d, J =9, 1H, amideH), and 6.2 (broad s, 1H, NH).

F. 3β-t-Butyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one

To a solution of t-butyloxycarbonylaminoazetidinone prepared asdescribed in E. above (11.88 g, 34.48 mmole) in 12 ml of THF was addedat 0° C. tetrabutylammonium fluoride (10.412 g, 39.5 mmole) and themixture was allowed to stir for about 1.5 hours. The reaction mixturewas evaporated under vacuum to obtain the product as an oil. The oil wasfiltered through 100 g of silica gel using 10% ethyl alcohol in ethylacetate. The filtrate was evaporated under vacuum to provide the productas a yellow solid. The solid was mixed with hexane, sonicated, andfiltered to yield 6.28 g of the 4β-(2-hydroxyethyl)azetidinone as awhite solid (79.5% yield). The product was shown to be pure cis isomerby its NMR spectrum.

90 MHz, NMR (CDCl₃, δ):1.4 (s, 9H, t-butyloxy), 1.7 (m, 2H, CH₂ H), 3.0(broad s, 1H, OH H), 3.7 (m, 2H, CH₂ H), 3.9 (m, 1H, C₄ H , 5.0 (dd, J=5 and 8, 1H, C₃ H), 5.8 (d, J =8, 1H, amide H), and 6.8 (broad s, 1H,NH).

G.3β-t-Butyloxycarbonylamino-4β-[2-(methylsulfonyloxy)ethyl]azetidin-2-one

To a solution of the 2-hydroxyethyl substituted azetidinone, prepared asdescribed in F. above (6.28 g, 27.424 mmole) in a mixture of 200 ml ofchloroform and 100 ml of dioxane were added triethylamine (11.1 g, 109.7mmole) and methanesulfonyl chloride (6.283 g, 54.85 mmole). The reactionmixture was stirred for one hour and was then poured into a mixture of300 ml of methylene chloride and 150 ml of a saturated sodiumbicarbonate solution. The organic phase was separated and the aqueousphase was washed twice with 150 ml of methylene chloride. The washes andthe organic layer were combined, dried over magnesium sulfate, filteredand evaporated under vacuum to yield an oily solid. The solid wastriturated with a mixture of diethyl ether and hexane, 50/50, filtered,dried to yield 8.4 g of the corresponding methanesulfonyloxy derivative.

H. 3β-t-Butyloxycarbonylamino-4β-(2-iodoethyl)azetidin-2-one

A solution of 8.4 g of the mesylate ester prepared as described in G.above (27.3 mmole) in 400 ml of acetone and containing sodium iodide(16.5 g, 110.0 mmole) was heated at the reflux temperature for 4 hours.Another 2 g of sodium iodide were added and the mixture was heated atthe reflux temperature for an additional hour. The reaction mixture wasevaporated under vacuum and the residue treated with methylene chloride.The insoluble material was filtered and the filtrate was concentratedunder vacuum to a brownish oil. The oil was dissolved in 80% ethylacetate/hexane and filtered through 200 g of silica gel. The filtratewas evaporated to yield 7.65 g of the product as a yellowish solid. Thesolid was dissolved in the minimum amount of hot ethyl acetate and thewarm solution diluted with hexane. The product precipitated to yield 4.9g of a first crop of the 2-iodoethyl compound as a white solid and 1.65g as a second crop (70.6% yield).

90 MHz NMR (CDCl₃, δ): 1.4 (s, 9H, t-butyloxy H), 2.1 (m, 2H, CH₂ H),3.1 (t, J =5, 2H, CH₂ I H), 3.9 (dt, J =5 and 7, 1H, C₄ H), 5.1 (m, 2H,C₄ H and amide H), and 6.2 (broad s, 1H, NH).

    .sub.D.sup.25 [α]=+50.65

IR (CHCl₃) 1770 cm⁻¹ (β-lactam carbonyl). Elemental analysis calculatedfor C₁₀ H₁₇ N₂ O₃ I:

    ______________________________________                                                    Theory     Found                                                  ______________________________________                                        C             35.31        35.52                                              H              5.04         4.74                                              N              8.24         8.08                                              ______________________________________                                    

I. t-Butyl7δ-t-butyloxycarbonylamino-3-methoxycarbonyl-1-carba-3-cephem-4-carboxylate

To a 50 ml round bottom flask, flame dried and flushed with drynitrogen, was added the 2-iodoethylazetidinone prepared as describedabove in H. (1.0 g, 2.941 mmole) and THF and the solution was cooled toa temperature of about -78° C. To the cold solution was addeddi-(trimethylsilyl)lithiumamide (2.82 ml, 2.822 mmole) and the mixturewas stirred in the cold for about 30 minutes. Next, via cannula, wasadded 2-phenylsulfinylmaleic acid 1-methyl 4-t-butyl diester (0.927 g,2.985 mmole) and the reaction mixture wa stirred for about 10-15minutes. 1,3-Dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone was addedto the reaction mixture which then was allowed to warm slowly to roomtemperature over about 2 hours. The reaction mixture was stirred at roomtemperature for about 45 minutes, poured into a mixture of 50 ml of anaqueous ammonium chloride solution and 150 ml of ethyl acetate. Theorganic phase was separated, dried over magnesium sulfate, filtered andevaporated under vacuum to a yellow oil. The oil was chromatographed on100 g of silica gel using 25% ethyl acetate/hexane for elution. Thefractions containing the desired product were combined and evaporatedunder vacuum to yield 560 mg of the product as a white foam. NMRindicated the product to be about 80% pure. The product was furtherpurified on preparative thick layer plates (4×2 mm) using 25% ethylacetate in hexane to give 520 mg of the title compound in about 90%purity.

90 MHz NMR (CDCl₃, δ): 1.4 (s, 9H, t-butyl H), 1.5 (s, 9H, t-butyl H),3.7 (s, 3H, COOCH₃ H), 3.9 (m, 1H, C₆ H), 4.9-5.1 (m, 2H, C₇ H and amideH).

Mass Spec. 396 (M⁺), 340 (M⁺ -C₄ H₈).

IR (CHCl₃, δ) 1781 cm ⁻¹ β-lactam carbonyl

Elemental analysis calculated for C₁₉ H₂₈ N₂ O₇

    ______________________________________                                                    Theory     Found                                                  ______________________________________                                        C             57.56        57.63                                              H              7.12         6.84                                              N              7.07         7.08                                              ______________________________________                                    

Preparation 5

7β-Phenoxyacetylamino-3-methoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylate

A portion of t-butyl7β-t-butoxycarbonylamino-3-methoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylateis treated with trifluoroacetic acid at 0° C. to provide7β-amino-3-methoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylic acidtrifluoroacetic acid salt. This material is dissolved in tetrahydrofuranand treated with 5 molar equivalents of pyridine followed by 1.25 molarequivalents of phenoxyacetylchloride to provide the title compound.

Preparation 6 Benzhydryl7β-Phenoxyacetylamino-3-methoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylate

A portion of the material from Preparation 4 is dissolved inacetonitrile and treated with diphenyldiazomethane to provide the titlecompound which is, in turn, used in Example 13.

Preparation 7 p-Nitrobenzyl7β-phenoxyacetylamino-3-isopropoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylate

A. 1-Isopropyl 4-p-nitrobenzyl 2-phenylsulfinylmaleic acid diester

The diester is prepared in a manner analogous to Preparation 3 whileesterifying the 1-carboxylic acid with isopropanol usingdicyclobenzylcarbodiimide and dimethylamino pyridine.

B. t-Butyl-7β-t-butoxycarbonylamino-3-iso-propoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylate

The cyclocondensation to provide this compound is prepared in a manneranalogous to Preparation 4(I).

C. Selective deprotection and reprotection

The compound produced in part B is treated with trifluoroacetic acid toprovide7β-amino-3-isopropoxycarbonyl-1-carba(dethia)-3-cephem-4-carboxylicacid. This compound is then acylated with phenoxyacetyl chloride as inPreparation 5 and esterified with 1.25 molar equivalents ofp-nitrobenzylbromide in the presence of 1.5 molar equivalents ofN-methylmorpholine in dimethylformamide to provide the title compoundwhich, in turn, is used directly in Example 14.

Example 12 Benzhydryl7β-(N-t-butoxycarbonyl)amino-1-carba-(dethia)-3-cephem-3-methoxycarbonyl-4-carboxylate

A) A 1.96 g sample of benzhydryl 7β-phenoxyacetylamino-1-carba(dethia)-3-cephem-3-methoxycarbonyl-4-carboxylate wasdissolved in 10 ml of CH₂ Cl₂ and treated with 490 mg of dimethylaminopyridine and 1.07 ml of di-t-butyl dicarbonate. Upon completion of thereaction, the crude mixture was diluted with 300 ml of ethyl acetate andwashed sequentially with 1N HCl (2 times), saturated sodium bicarbonate,brine, and dried over anhydrous magnesium carbonate.

NMR (300 MHz, CDCl₃): δ: 1.3, 1.8, 2.2 and 2.9 (m, 4H, C₁ --H and C₂--H); 1.5 (s, 9H, t-butyl); 3.2 (s, 3H, --OCH₃); 3.8 (m, 1H, C₆ --H);5.15 (s, 2H, φ--O--CH₂ --); 5.8 (d, J=7 Hz, 1H, C₇ --H); 6.9, 7.1 and7.4 (m, 15H, φ₂ --CH--and φ--O--); 7.15 (s, 1H, φ₂ --CH--).

Yield=2.29 g.

B) The imide produced in Step A was dissolved in 35 ml oftetrahydrofuran and treated with 2.68 ml of 1N lithium hydroxide. Afterstirring for 30 minutes, an additional 0.89 ml of 1N lithium hydroxidewas added. Finally, after an additional 30 minutes of stirring, anadditional 0.35 ml of lithium hydroxide was added. After 30 minutes, thereaction mixture was diluted with 300 ml of ethyl acetate and extractedsequentially with saturated sodium bicarbonate solution (3 times),brine, and dried over anhydrous magnesium sulfate. Chromatography over200 g of normal phase silica gel (5% ethyl acetate/CH₂ Cl₂) yielded 0.91g of the title compound.

NMR (300 MHz, CDCl₃) δ: 1.45 (s, 9H, t-butyl); 1.5, 2.2, 2.3 and 2.9 (m4H, C₁ --H and C₂ --H); 3.3 (s, 3H, --OCH₃) ; 3.9 m, 1H, C₆ --H); 5.05(bd, J=6 Hz, 1H, t-butoxycarbonyl-N-H); 5.3 (m, 1H, C₇ --H); 7.1 (s, 1H(C₆ H₅)₂ --C--H); 7.4 (m, 10H, (C₆ H₅₋₋₂).

Example 13 p-Nitrobenzyl7β-(N-t-butoxycarbonyl)amino-1-carba(dethia)-3-cephem-3-isopropoxycarbonyl-4-carboxylate

In a procedure analogous to that of Example 13, the title compound wasproduced in 57% overall yield.

NMR (300 MHz, CDCl₃) δ: 1.2 (d, J=7 Hz, 6H, --CHCH₃) ; 1.42 (s, 9H,t-butyl); 1.45, 2.15, 2.3 and 2.85 (m, 4H, C₁ --H and C₂ --H), 3.9 (m,1H, C₆ --H); 5.05 (heptet, J=7 Hz, 1H, --CH(CH₃)₂); 5.0 (bm, 1H); 5.2(bm, 1H); 5.4 (AB, J=15 Hz, 2H, --CH₂ --C₆ H₄ --NO₂) ; 7.6 (d, J=9 Hz,2H); 8.2 d, J=9 Hz, 2H).

Example 141-(1-Methoxycarbonyl-2-methylprop-1-ene-1-yl)-3β-(t-butoxycarbonyl)amino-1-ylazetidin-2-one

A solution of1-(1-methoxycarbonyl-2-methylprop-1-ene-1-yl)-3β-(phenoxyacetyl)amino-1-ylazetidin-2-one in THF is treated with 1.2 molar equivalents ofdi-t-butyldicarbonate, 1.0 molar equivalent of triethylamime, and 0.05molar equivalent of dimethylamino pyridine to provide1-(1-methoxycarbonyl-2-methylprop-1-ene-1-yl)-3β-(t-butoxycarbonyl,phenoxyacetyl)amino-1-yl azetidin-2-one.

The disubstituted compound from above is then treated with lithiumhydroxide in THF to provide the title compound.

We claim:
 1. A compound of the formula ##STR28## wherein R isallyloxycarbonyl, t-butoxycarbonyl, naphthyloxycarbonyl,trichloroethyloxycarbonyl, p-nitro benzyloxycarbonyl,benzhydryloxycarbonyl, p-methoxybenzyl oxycarbonyl,o-nitrobenzyloxycarbonyl or acetoxy; wherein R⁴ is phenoxyacetyl,phenylacetyl, C₁ to C₆ alkanoyl or chloracetyl, and wherein A and A' aretaken together to form a group of the formula ##STR29## wherein R¹ is acarboxy-protecting group; X is sulfur and R² is hydrogen, halo, C₁ to C₆alkyl, C₁ to C₆ alkyl substituted by one or two halogen, hydroxy,protected hydroxy, amino, protected amino, C₁ to C₇ acyloxy, nitro,carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano,methylsulfonylamino or C₁ to C₄ alkoxy; C₁ to C₆ alkylthio, C₁ to C₆alkylthio substituted by one or two halogen, hydroxy, protected hydroxy,amino, protected amino, C₁ to C₇ acyloxy, nitro, carboxy, protectedcarboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or C₁ to C₄alkoxy; C₇ to C₁₂ arylalkyl, C₇ to C₁₂ arylalkyl substituted on thealkyl position with one or two groups chosen from halogen, hydroxy,protected hydroxy, amino, protected amino, C₁ to C₇ acyloxy, nitrocarboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, C₁ to C₆alkylthio, methylsulfonylamino or C₁ to C₄ alkoxy; and/or the phenylgroup of the arylalkyl being substituted with 1 to 2 groups chosen fromhalogen, hydroxy, protected hydroxy, nitro, C₁ to C₆ alkyl, C₁ to C₄alkoxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl,protected aminomethyl, or methylsulfonylamino; phenyl or phenylsubstituted with one or two moieties chosen from the group consisting ofhalogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ toC₄ alkoxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl,protected aminomethyl, trifluoromethyl or methylsulfonylamino;a group ofthe formula

    --CY.sub.3

wherein Y is fluoro, chloro, bromo or iodo; a group of the formula it--COR⁶ wherein R⁶ is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ alkylsubstituted by one or two halogen, hydroxy, protected hydroxy, amino,protected amino, C₁ to C₇ acyloxy, nitro, carboxy, protected carboxy,carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or C₁ to C₄ alkoxy;C₇ to C₁₂ arylakyl, C₇ to C₁₂ arylakyl substituted on the alkyl positionwith one or two groups chosen from halogen, hydroxy, protected hydroxy,amino, protected amino, C₁ to C₇ acyloxy, nitro, carboxy, protectedcarboxy, carbamoyl, carbamoyloxy, cyano, C₁ to C₆ alkylthio,methylsulfonylamino or C₁ -C₄ alkoxy; and/or the phenyl group of thearylakyl being substituted with 1 or 2 groups chosen from halogen,hydroxy, protected hydroxy, nitro, C₁ to C₆ alkyl, C₁ to C₄ alkoxy,carboxy, protected carboxy, carboxymethyl protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, or methylsulfonylamino; phenyl, phenyl substituted with oneor two moieties chosen from the group consisting of halogen, hydroxy,protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ to C₄ alkoxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl or methylsulfonylamino; amino, aminosubstituted once with C₁ to C₆ alkyl, C₇ to C₁₂ arylalkyl, phenyl, orphenyl substituted with one or two moieties chosen from the groupconsisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ toC₆ alkyl, C₁ to C₄ alkoxy, carboxy, protected carboxy, carboxymethyl,protected carboxymethyl, hydroxymethyl, protected hydroxymethyl,aminomethyl, protected aminomethyl, trifluoromethyl ormethylsulfonylamino; or amino substituted with two substituents chosenfrom the group consisting of C₁ to C₆ alkyl, C₇ to C₁₂ arylalkyl;phenyl, phenyl substituted with one or two moieties chosen from thegroup consisting of halogen, hydroxy, protected hydroxy, cyano, nitro,C₁ to C₆ alkyl, C₁ to C₄ alkoxy, carboxy, protected carboxy,carboxymethyl, protected carboxymethyl, hydroxymethyl, protectedhydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl ormethylsulfonylamino; or R² is a group of the formula

    --COOR.sup.7

wherein R⁷ is hydrogen, an organic or inorganic cation, C₁ to C₆ alkyl,C₁ to C₆ alkyl substituted by one or two halogen, hydroxy, protectedhydroxy, amino, protected amino, C₁ to C₇ acyloxy, nitro, carboxy,protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylaminoor C₁ to C₄ alkoxy; C₇ to C₁₂ arylakyl, C₇ to C₁₂ arylalkyl substitutedon the alkyl position with one or two groups chosen from halogen,hydroxy, protected hydroxy, amino, protected amino, C₁ to C₇ acyloxy,nitro carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, C₁ toC₆ alkylthio, methylsulfonylamino or C₁ -C₄ alkoxy, and/or the phenylgroup of the arylalkyl being substituted with 1 or 2 groups chosen fromhalogen, hydroxy, protected hydroxy, nitro, C₁ to C₆ alkyl, C₁ to C₄alkoxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl,protected aminomethyl, or methylsulfonylamino; a carboxy-protectinggroup or a non-toxic metabolically-labile, ester-forming group; or R₂ isa group of the formula

    --CH.sub.2 --S--"Heterocyclic";

or R₂ is a group of the formula

    --S--"Heterocyclic"

said "heterocyclic" being an optionally substituted 5-membered or6-membered ring having 1 to 4 heteroatoms selected from oxygen, sulfur,or nitrogen, said heterocyclic optionally fused to an aromatic5-membered or 6-membered ring;

    --OR.sup.9

wherein R⁹ is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ alkyl substituted byone or two halogen, hydroxy, protected hydroxy, amino, protected amino,C₁ to C₇ acyloxy, nitro, carboxy, protected carboxy, carbamoyl,carbamoyloxy, cyano, methylsulfonylamino or C₁ to C₄ alkoxy; C₇ to C₁₂arylalkyl, C₇ to C₁₂ arylalkyl substituted on the alkyl position withone or two groups chosen from halogen, hydroxy, protected hydroxy,amino, protected amino, C₁ to C₇ acyloxy, nitro carboxy, protectedcarboxy, carbamoyl, carbamoyloxy, cyano, C₁ to C₆ alkylthio,methylsulfonylamino; or C1-C4 alkoxy; and/or the phenyl group of thearylalkyl being substituted with 1 or 2 groups chosen from halogen,hydroxy, protected hydroxy, nitro, C₁ to C₆ alkyl, C₁ to C₄ alkoxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, or methylsulfonylamino; phenyl, phenyl substituted with oneor two moieties chosen from the group consisting of halogen, hydroxy,protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ to C₄ alkoxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl or methylsulfonylamino; or C₁ to C₇.
 2. Acompound of claim 1 wherein X is --CH₂ --. t-butoxycarbonyl.
 3. Acompound of claim 2 wherein R⁴ is phenoxyacetyl.